title: Time-dependent pharmacokinetics of 5-fluorouracil and association with treatment tolerability in the adjuvant setting of colorectal cancer.
abstract: The authors evaluated the influence of 5-fluorouracil (5-FU) on treatment tolerability in 81 colorectal cancer patients given adjuvant 5-FU intravenously plus folinic acid for 6 cycles. The pharmacokinetics of 5-FU and its inactive metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) were measured on days 1 and 5 of the first chemotherapy cycle, 5 and 45 minutes after bolus administration. 5-FU clearance was significantly lower on day 5 (62.64 ± 20.16 L/h/m(2)) than on day 1 (74.83 ± 31.61 L/h/m(2)). The lower 5-FU clearance values also predicted the side effects during the entire course of chemotherapy. In particular, patients with low clearance values on day 1 had a further reduction in this parameter on day 5, associated with severe toxicities. In conclusion, 5-FU alters its clearance, which could be partly due to a reduction in 5-FDHU biotransformation. These findings have safety implications for poor metabolizers whose drug clearance may fall below the threshold during repeated treatment cycles.
authors.affiliation: Osteoncology Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy.
authors.forename: Toni
authors.initials: T
authors.lastname: Ibrahim
authors.forename: Antonello
authors.initials: A
authors.lastname: Di Paolo
authors.forename: Federica
authors.initials: F
authors.lastname: Amatori
authors.forename: Laura
authors.initials: L
authors.lastname: Mercatali
authors.forename: Elena
authors.initials: E
authors.lastname: Ravaioli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Flamini
authors.forename: Emanuele
authors.initials: E
authors.lastname: Sacanna
authors.forename: Mario
authors.initials: M
authors.lastname: Del Tacca
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000970:Antineoplastic Agents; C019389:5-fluorodihydrouracil; D005472:Fluorouracil